Many pain syndromes/disorders observed below the head region, such as irritable bowel syndrome (IBS), fibromyalgia, interstitial cystitis (1C), vulvodynia, endometriosis and pelvic pain, have a greater prevalence in women or are female-specific. The long-term goal of our research is to enhance understanding of the biological mechanisms that contribute to sex-related differences in the perception and control of spinal nociception. Although partial kappa opioid agonists have been shown to produce a greater analgesic effect in women than in men in a clinical model of trigeminal pain, a growing literature in the spinal cord has not produced a clear picture. Furthermore, partial kappa opioids used in clinical trials also have affinity for the mu opioid receptor (MOR). The present proposal is, therefore, designed to test the hypotheses that (!) selective activation of the kappa opioid receptor (KOR) in the dorsal horn of the spinal cord produces enhanced antinociception in the female as compared to male rats, and (ii) estrogen plays a critical role in enhancing the antinociceptive effects in the female by increasing the expression of the gene for the kappa opioid receptor in the spinal cord. Aim 1 determines whether selective activation of the kappa opioid receptor in the spinal cord produces sex-specific modulation of spinal nociception in an estrogen-dependent manner. Using behavioral tests, the effect of kappa agonists will be tested in the absence and presence of kappa opioid receptor (KOR) blockade using selective antagonists as well as antisense knockdown of the KOR in the spinal cord. Aim 2 will determine electrophysiologically the neuronal subtypes in the spinal dorsal horn that underlie the estrogendependent sex-specific modulation of spinal nociception. Aim 3 will determine whether the increased expression of the kappa opioid receptor gene contributes to the molecular basis for the estrogen-dependent enhanced antinociceptive effects in the spinal cord. The proposed studies should provide fundamental new knowledge regarding the role of KOR in pain suppression in the spinal cord, and a new perspective in the treatment of pain, particularly in women at different phases of their life (pre-puberty, reproductive years, pregnancy, menopause) via activation of KOR, receptors whose activation is not linked to addictive side-effects characteristic of other opioid receptor subpopulations.